Purpose of review Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major public health threat globally. Several lines of evidence support a role for host genetic factors in resistance/susceptibility to TB disease and MTB infection. However, results across candidate gene and genome-wide association studies (GWAS) are largely inconsistent, so a cohesive genetic model underlying TB risk has not emerged. Recent Findings Despite the difficulties in identifying consistent genetic associations, genetic studies of TB and MTB infection have revealed a few well-documented loci. These well validated genes are presented in this review, but there remains a large gap in how these genes translate into better understanding of TB. To address this, we present a pathway based extension of standard association analyses, seeding the results with the best validated genes from candidate gene and GWAS studies. Summary Several pathways were significantly enriched using pathway analyses that may help to explain population patterns of TB risk. In conclusion, we advocate for novel approaches to the study of host genetic analysis of TB that extend traditional association approaches.

Increased expression of cytochrome P450 CYP2C9, together with elevated levels of its products epoxyeicosatrienoic acids (EET), is associated with aggressiveness in cancer. Cytochrome P450 variants and encode proteins with reduced enzymatic activity, and individuals carrying these variants metabolize drugs more slowly than individuals with wild-type , potentially affecting their response to drugs and altering their risk of disease. Although genetic differences in CYP2C9-dependent oxidation of arachidonic acid (AA) have been reported, the roles of CYP2C9*2 and CYP2C9*3 in EET biosynthesis and their relevance to disease are unknown. Here, we report that CYP2C9*2 and CYP2C9*3 metabolize AA less efficiently than CYP2C9*1 and that they play a role in the progression of non-small cell lung cancer (NSCLC) via impaired EET biosynthesis. When injected into mice, NSCLC cells expressing CYP2C9*2 and CYP2C9*3 produced lower levels of EETs and developed fewer, smaller, and less vascularized tumors than cells expressing CYP2C9*1. Moreover, endothelial cells expressing these two variants proliferated and migrated less than cells expressing CYP2C*1. Purified CYP2C9*2 and CYP2C9*3 exhibited attenuated catalytic efficiency in producing EETs, primarily due to impaired reduction of these two variants by NADPH-P450 reductase. Loss-of-function SNPs within and were associated with improved survival in female cases of NSCLC. Thus, decreased EET biosynthesis represents a novel mechanism whereby CYPC29*2 and CYP2C9*3 exert a direct protective role in NSCLC development. These findings report single nucleotide polymorphisms in the human CYP2C9 genes, and, exert a direct protective role in tumorigenesis by impairing EET biosynthesis. .

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Globally, lung cancer results in more deaths worldwide than any other cancer, indicating a need for better treatments. Members of the eicosanoid metabolism pathway represent promising therapeutic targets, as several enzymes involved in the generation of these lipids are dysregulated in many cancers and their inhibition reduces lung cancer growth in mouse models. However, genetic variation of enzymes involved in eicosanoid metabolism has not been adequately examined for association with lung cancer. The goal of this study was to determine whether germline genetic variation altering eicosanoid producing enzyme function and/or expression are associated with differences in lung cancer survival. We examined the association of genetic variation with mortality within eicosanoid metabolism genes in 395 non-small-cell lung cancer (NSCLC) cases from the Southern Community Cohort Study (SCCS). A total of 108 SNPs, both common and rare, in 19 genes, were examined for association. No common or rare variants were associated with lung cancer survival across the entire study population. However, rare variants in ALOX15B (arachidonate 15-lipoxygenase, type B) and the common variant rs12529 in AKR1C3 (prostaglandin F synthase) were associated with NSCLC mortality in women and African Americans, respectively. Rare variants in ALOX15B were associated with greater mortality in women (HR = 2.10, 95% CI = 1.25–3.54, p-value = 0.005). The major allele of rs12529 in AKCR1C3 associated with improved survival in African Americans (HR = 0.74, 95% CI = 0.59–0.92, p-value = 0.008). The lack of genetic associations among all NSCLC cases and the association among women only for rare variants in ALOX15B may, in part, explain the better NSCLC survival observed among women. These results raise the possibility that some subgroups within the NSCLC population may benefit from drugs targeting eicosanoid metabolism.

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